tbuckley/cabot-search huggingface dataset:
Abstract A013: Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma
Authors: David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR015) of the Conference Program/Proceedings. Citation Format: David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri. Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A013.
Abstract B020: A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma
Authors: Ilaria Delle Fontane, Nuri Damayanti, Christopher Rupert, David E. Heppner, Roberto Pili
Journal: Cancer Research (2023)

Abstract TFE3 is a member of basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are linked to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, molecular cloning, next generation transcriptomics, FRET technology, mutagenesis, proteomics, and high-throughput high-content screening (HTHCS) we interrogated a series of oncogenic mechanisms of TFE3-SF-containing fusions, including spontaneous nuclear translocation, nuclear paraspeckle occupancy, enhanced in vitro proliferation and in vivo growth, transcriptome remodeling, alternative splicing reprogramming, and novel dimer partner recruitment. Molecular inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. Using HTHCS combined with FRET technology we screened FDA approved drugs library (LOPAC) and small molecule library (Microsource) and identified hits compounds which inhibit TFE3-SF dimerization. Hits compounds were validated in 2D and 3D models utilizing patient derived xenolines expressing TFE3-SF. Ouabain and terfenadine demonstrated decreased cell proliferation reduced spheroid growth and in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer. Citation Format: Ilaria Delle Fontane, Nuri Damayanti, Christopher Rupert, David E. Heppner, Roberto Pili. A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B020.
Abstract IA004: Identification of potential new therapeutic targets in kidney cancer
Authors: Qing Zhang
Journal: Cancer Research (2023)

Abstract VHL is the most important tumor suppressor in clear cell renal cell carcinoma (ccRCC). In the majority of ccRCC, as a result of VHL loss, HIF2a stabilization is sufficient and necessary for promoting ccRCC tumor growth. Despite the development of HIF2a specific inhibitors, the intrinsic and extrinsic resistance do exist, highlighting the importance of identifying additional therapeutic vulnerabilities in ccRCC. We have recently performed some genome-wide screening and identified new signaling pathways regulated by VHL, including ZHX2 and SFMBT1 that play important roles in ccRCC. In addition, we also identified some synthetic lethality binding partners for VHL loss in kidney cancer, including TBK1. However, it is challenging to target TBK1 in clinical practice due to lack of selectivity for TBK1 inhibitors and its role involved in innate immune signaling. To overcome this difficulty, one approach would be to identify a critical upstream regulator of TBK1 that can be targeted therapeutically, especially in ccRCC displaying hyper-activated TBK1 activity due to VHL loss. We have performed a kinome-wide screening and identified Doublecortin like kinase 2 (DCLK2), an enigmatic kinase involved in neuronal survival and growth cone regeneration upon injury, as a novel TBK1 regulator in ccRCC. Our functional assays demonstrate that DCLK2 is necessary and sufficient to promote ccRCC tumorigenesis through activating TBK1. In addition, we also characterized a DCLK2 short isoform (DCLK2203) that play a predominant role in ccRCC tumorigenesis. Our work suggests that DCLK2 is a novel TBK1 activator and potential therapeutic target in ccRCC. Citation Format: Qing Zhang. Identification of potential new therapeutic targets in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA004.
Abstract A019: Development and characterization of novel pre-clinical models of SFPQ-TFE3-driven renal cell carcinoma
Authors: Adrianna Amaral de Aragao Mendes, Hans Liu, Juhyung Woo, Kaushal Asrani, Avi Rosenberg, Pedram Argani, Tamara Lotan
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR001) of the Conference Program/Proceedings. Citation Format: Adrianna Amaral de Aragao Mendes, Hans Liu, Juhyung Woo, Kaushal Asrani, Avi Rosenberg, Pedram Argani, Tamara Lotan. Development and characterization of novel pre-clinical models of SFPQ-TFE3-driven renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A019.
Abstract PR007: Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis
Authors: Cheng Zhang, Zhao Zhang, Austin Hepperla, Miaomiao Yu, Jin Zhou, Lianxin Hu, Jun Fang, Qian Liang, Kexin Xu, Liwei Jia, Qing Zhang
Journal: Cancer Research (2023)

Abstract Background: Renal cancer is the most common adult genitourinary cancer, of which ~85% is accounted for by the clear cell subtype (ccRCC). In the majority of ccRCC, as a result of VHL loss, HIF2a stabilization is sufficient and necessary for promoting ccRCC tumor growth. However, HIF-2 inhibitors have limited efficacy in cancer therapy, highlighting the importance of identifying additional therapeutic vulnerabilities. N6-Methyladenosine (m6A) is the most abundant internal post-translation modification, and its contribution to cancer evolution has just been appreciated. In renal cancer, previous research showed that m6A may play an important role but the molecular mechanism underlying m6A-regulated ccRCC tumorigenesis and aggression is still obscure. Approach and results: We demonstrate that VHL binds with m6A enzymatic complex proteins and regulates METTL3-METTL14 complex formation. VHL depletion suppresses mRNA m6A modification. By performing m6A RIP-Seq for renal cells with or without VHL coupled with RNA-Seq, we identified a selection of genes that their expression may be regulated by m6A. Specifically, PIK3R3 was identified to be one critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promoted renal cell growth and tumor growth while vice versa. Mechanistically, the VHL-m6A regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Conclusion: Taken together, we propose a new mechanism by which VHL regulates m6A through modulating METTL3-METTL14 protein complex formation, therefore promoting PIK3R3 mRNA stability and protein level that is critical for regulating ccRCC tumorigenesis. Citation Format: Cheng Zhang, Zhao Zhang, Austin Hepperla, Miaomiao Yu, Jin Zhou, Lianxin Hu, Jun Fang, Qian Liang, Kexin Xu, Liwei Jia, Qing Zhang. Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR007.
Abstract B008: Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma
Authors: Romain Riscal, Sarah Gardner, Madeleine Carens, Clementina Mesaros, Jimmy Xu, Nate Coffey, Leah Davis, Austin Vogt, Adam Olia, Jennifer Finan, Jason Godfrey, Ian Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, Celeste Simon
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. We and others have demonstrated that elevated lipid uptake and storage is required for ccRCC cell viability; however, the role of stored cholesterol, the most abundant component in ccRCC intracellular lipid droplets, remains unclear. We recently demonstrated that ccRCC cells acquire exogenous cholesterol through the HDL receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we show that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is essential for ccRCC cell survival. Repressing HSD3B7 expression genetically, or treating ccRCC cells with a newly identified HSD3B7 inhibitor, resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. Citation Format: Romain Riscal, Sarah Gardner, Madeleine Carens, Clementina Mesaros, Jimmy Xu, Nate Coffey, Leah Davis, Austin Vogt, Adam Olia, Jennifer Finan, Jason Godfrey, Ian Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, Celeste Simon. Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B008.
Abstract B004: Serine promotes invasive phenotype through enhanced translation of SNAIL in ccRCC
Authors: Suman Karki
Journal: Cancer Research (2023)

Abstract Background: Metastatic clear cell renal cell carcinoma (ccRCC) is the most common type of renal carcinoma with a median survival rate of about 13 months and is refractory to chemotherapy. ccRCC is fundamentally a metabolic disease characterized by extensive reprogramming in amino acid metabolism. Serine is a nonessential amino acid (NEAA), and the serine biosynthetic pathway has been shown as an essential source of metabolic intermediates in many cancers. Analysis of the TCGA database reveals that ccRCC tumors have reduced levels of PHGDH, the first enzyme in the de novo serine biosynthesis pathway, and makes serine conditionally essential amino acid in these tumors. The role of serine in tumorigenesis is well established; however, its role in promoting invasive phenotype and metastasis is not explored. Methods: To gain insight into the role of nonessential amino acids in proinvaisive phenotypes, we performed wound healing and migration assays in the presence of individual NEAAs. The importance of serine synthesis for promoting invasive phenotype was also assessed by restoring PHGDH in low PHGDH ccRCC. Results: In an unbiased approach, we found that serine is required for the increased migratory and invasive phenotype in ccRCC. We also demonstrate that in low PHGDH ccRCC cells, exogenous serine is to maintain SNAIL expression and the enhanced migratory and invasive phenotype. We also show that serine depletion induces translational inhibition in low PHGDH ccRCC. Conclusion: The role of serine in tumorigenesis and cell proliferation is well established; however, its role in supporting invasive and metastatic phenotypes is previously unknown. Our data highlights a novel role for serine in promoting EMT through enhanced translational maintenance of SNAIL, which may be therapeutically targeted in ccRCC. Citation Format: Suman Karki. Serine promotes invasive phenotype through enhanced translation of SNAIL in ccRCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B004.
Abstract B033: Targeting acquired resistance to HIF2α inhibition in kidney cancer
Authors: Fangzhou Zhao, Jeremy Simon, Qing Zhang
Journal: Cancer Research (2023)

Abstract Recently, a HIF-2α inhibitor MK-6482 was developed and approved by FDA to treat certain patients with VHL disease-associated RCC. However, in preclinical studies, both intrinsic and adaptive resistance to this drug was reported, which highlights the necessity of uncovering the mechanisms underlying drug resistance and developing alternative treatments for HIF-2α inhibitor-resistant patients. To this end, we established several 786-O cell lines that are resistant to PT2399 (analog of MK-6482) treatment. To characterize the differences between sensitive and resistant cell lines, we performed RNA sequencing, Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and CUT&amp;RUN sequencing experiments. Through integrative analyses of all sequencing data, we identified a series of candidate genes which might contribute to the acquirement of drug resistance for further validation. We identified 2'-5'-oligoadenylate synthetase 2 (OAS2) as one of the candidate genes exhibiting both significant upregulation in RNA level and dramatically increased chromatin accessibility in the promoter region in resistant lines comparing to sensitive lines. We further validated the upregulation of OAS2 mRNA level as well as protein level in all resistant clones by RT-qPCR and western blot, respectively. OAS2 belongs to 2-5A synthetase family, which is involved in the activation of latent RNase L and degradation of viral RNA during innate immune response to viral infection. Interestingly, the other 3 members in this protein family, OAS1, OAS3 and OASL, are also significantly upregulated at RNA level in resistant cell lines, although the upregulation of chromatin accessibility is modest. Furthermore, OAS2, along with the other 3 family members, all show increased expression levels in ccRCC tumor tissues comparing to normal tissues. Therefore, we hypothesize that OAS2 protein promotes ccRCC cell proliferation under HIF-2α inhibitor treatment, thus contributing to the adaptive resistance to HIF-2α inhibitor. We will test this hypothesis through a series of loss-of-function and gain-of-function experiments, while continuing to investigate other candidate genes. Citation Format: Fangzhou Zhao, Jeremy Simon, Qing Zhang. Targeting acquired resistance to HIF2α inhibition in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B033.
Abstract IA001: Evidence for a ‘pathway tuning’ model of VHL-associated renal carcinoma
Authors: Peter J. Ratcliffe
Journal: Cancer Research (2023)

Abstract In clear cell renal carcinoma (RCC), the hypoxia inducible factor (HIF) transcriptional response is unphysiologically activated by mutations that impair or inactivate the von Hippel-Lindau tumour suppressor, which normally acts as a ubiquitin E3 ligase promoting the oxygen dependent proteolysis of hypoxia inducible factor (HIF). The lecture will review evidence for pro- and anti-tumourigenic actions arising from different components of HIF pathway activation in the setting of VHL-associated RCC. This includes evidence from genome-wide association studies (GWAS) that demonstrate a striking association of GWAS signals with cis-acting sequences in the HIF transcriptional system. This supports a ‘pathway tuning’ model in which multiple small selective effects are important in enabling cancer progression in the face of unphysiological activation of very extensive biological pathways. To assess this hypothesis a new experimental model has been developed, which enables the precise tracking of Vhl-inactivated cells. Results on the temporal and spatial effects of Vhl inactivation in kidneys will be presented. Citation Format: Peter J. Ratcliffe. Evidence for a ‘pathway tuning’ model of VHL-associated renal carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA001.
Abstract A003: Kinome-wide siRNA screening identifies DCLK2 as a TBK1 activator and therapeutic target for ccRCC
Authors: Lianxin Hu, Qing Zhang
Journal: Cancer Research (2023)

Abstract TBK1 has been identified as a potential therapeutic target in multiple cancers. However, it is challenging to target TBK1 in clinical practice due to lack of selectivity for TBK1 inhibitors and its role involved in innate immune signaling. To overcome this difficulty, one approach would be to identify a critical upstream regulator of TBK1 that can be targeted therapeutically, especially in clear cell Renal Cell Carcinoma (ccRCC) displaying hyper-activated TBK1 activity due to VHL loss. In this study, we perform a kinome-wide siRNA screening and identify Doublecortin like kinase 2 (DCLK2) as a novel TBK1 regulator in ccRCC. DCLK2 binds with TBK1 and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage independent colony growth of kidney cancer cells as well as kidney tumorigenesis in orthotopic xenograft models. DCLK2 gene product contains multiple isoforms. Among them, a short isoform called DCLK2203 expresses predominantly in ccRCC. Overexpression of DCLK2203 promotes ccRCC cell growth and tumorigenesis in vivo, which elicits its oncogenic signaling via activating TBK1 phosphorylation. Taken together, our work suggest that DCLK2 is a novel TBK1 activator and potential therapeutic target for ccRCC. Citation Format: Lianxin Hu, Qing Zhang. Kinome-wide siRNA screening identifies DCLK2 as a TBK1 activator and therapeutic target for ccRCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A003.
Abstract PR012: SETD2 safeguards the genome against isochromosome formation
Authors: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell
Journal: Cancer Research (2023)

Abstract Chromosome mis-segregation during cell division occurs in diverse tumor types, promoting aneuploidy and intratumoral genetic heterogeneity. While the mechanisms that govern chromosome segregation are well-established, how changes in the activities of tumor suppressors or oncogenes drive mitotic errors remain poorly understood. Loss of the tumor suppressor SETD2, the methyltransferase responsible for tri-methylation of histone 3 lysine 36 (H3K36me3), correlates with clear cell renal cell carcinoma (ccRCC) tumors exhibiting extensive intratumoral heterogeneity. Yet, how loss of H3K36me3 or SETD2 promotes heterogeneity is unknown. Here, we show that loss of SETD2 promotes chromosome mis-segregation during mitosis and interphase DNA bridges driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these dicentrics loss were largely comprised of mirror-imaged isodicentric chromosomes that contain two active centromeres. In addition to isodicentrics, cells lacking SETD2 or H36K36me3 generated iso- and acentric chromosomes, however loss of SETD2 protein additionally caused chromosome instability. These data directly link loss of a tumor suppressor to these mutable chromatin structures that initiate intratumor heterogeneity by promoting gross chromosomal rearrangements. Citation Format: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell. SETD2 safeguards the genome against isochromosome formation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR012.